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ERIC 2020 | RESONATE-2 follow up: ibrutinib and chlorambucil 5 years on

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Jan Burger

Jan Burger, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, TX, discusses the follow up to the RESONATE-2 trial (NCT01722487, NCT01724346), which investigates the use of ibrutinib and chlorambucil for chronic lymphocytic leukemia (CLL). Five years after the initial investigation, 70% of participants taking ibrutinib showed progression-free survival compared to 12% with chlorambucil. Those in higher-risk groups also showed equal survival to those in lower-risk groups. This interview took place during the European Research Initiative on CLL (ERIC) International Virtual Meeting 2020.

Transcript (edited for clarity)

We did this RESONATE-2 study quite a long time ago. In the randomized study, we compared treatment with… At the time, chlorambucil as a single agent was still acceptable and patients were randomized to receive either chlorambucil or ibrutinib and those patients were treated around 2013, 2014. And now, we have longer follow-up on this study in previously untreated CLL patients. And the point to maybe update that after the initial publication several years ago...

We did this RESONATE-2 study quite a long time ago. In the randomized study, we compared treatment with… At the time, chlorambucil as a single agent was still acceptable and patients were randomized to receive either chlorambucil or ibrutinib and those patients were treated around 2013, 2014. And now, we have longer follow-up on this study in previously untreated CLL patients. And the point to maybe update that after the initial publication several years ago. And then was published earlier this year in Leukemia, was to say, how durable are these responses? And they are. Where we have at five years, we have a progression-free survival in ibrutinib treated patients of approximately 70%. So, that’s a major difference to the control arm. Patients are surviving without active disease for a long period of time.

And the other point in this study was with this long follow-up, we can also say that higher risk patients are doing as well as the low-risk patients. We didn’t have all the risk groups in this study. We excluded, on purpose, 17p-deleted patients because we felt they shouldn’t be randomized to receive chlorambucil. So, those patients are excluded. But we have mutated and unmutated; we have 11q-deleted and undeleted patients in this study. And on the ibrutinib arm, those patients with a higher risk disease feature, which is presence of 11q-deletion, presence of unmutated IGHV, those patients were doing as well as their counterparts with, what we used to call lower risk. And all these risk categories are based on chemotherapy. So, what we’ve learned now with the new agents is when you have an effective treatment, those risk factors from the past, lose their importance and are becoming much less important.

So, I think that was another important lesson. One question with these long-term treatments also becomes, how many patients can stay on study, how many drop off, either because of disease progression or because of side-effects, those data and in this study as well… And there, the short message is, there are more patients coming off study because of side effects than building up a resistance to the treatment, which is uncommon in the frontline disease setting. And the other message is still a majority more than 50% of patients were still on treatment at this later follow-up but some patients over time came off because of toxicities.

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